Obstructive sleep apnea (OSA) afflicts > 5% of adults and is associated with a 2 to 4-fold increased risk of cardiovascular disease (CVD). Small, short term studies have provided preliminary evidence that treatment of OSA with positive airway pressure (PAP) improves CVD risk factors. Given the high prevalence of OSA and its profound physiological disturbances, effective treatment could be expected to significantly reduce CVD burden in these patients. However, the role of PAP for primary or secondary prevention of CVD is unclear due to both concerns about long-term PAP adherence and the relative absence of rigorously designed large-scale prospective clinical trials evaluating the impact of OSA treatment on clinical endpoints. We have assembled a multi-disciplinary investigator team to address the critical study design issues relevant for launching a later large-scale Phase 3 randomized controlled trial (RCT). In this planning study, we propose to conduct a Phase 2 RCT which includes evaluation of alternative study design features such as the choice of control arms, approaches for optimizing PAP adherence, and choice of study endpoints. We aim to recruit patients with moderate to severe OSA and with CVD risk factors or established CVD from a network of large, regional sleep disorders centers. After a 2-week run-in period, 180 participants will be randomized to one of 3 intervention arms: an active PAP treatment arm or one of two control arms (sham-CPAP vs. conservative medical therapy, CMT). The use of two control arms will allow assessment of the trade-offs of using alternative control interventions that pose different levels of burden and allow different degrees of blinding. Alternative approaches for enhancing adherence to PAP, one of which includes an augmented behavioral-based intervention, also will be evaluated through a second-stage randomization procedure. All participants will undergo a standardized assessment of CVD risk factors at baseline and at 12 months, including measurement of 24 hour blood pressure, arterial tonometry, cardiac echocardiography, bioassays for markers in CVD pathogenesis pathways, and patient-reported outcomes. Interim monitoring for safety and adherence will be performed every two months. Analyses will: 1) quantify the retention and adherence rates, recruitment yields, and safety parameters within each study arm; 2) compare changes in the primary clinical outcome, average systolic blood pressure, across arms; 3) estimate effect sizes for changes in other intermediate markers and patient-reported outcomes; and 4) explore subgroup differences in responses. The proposed data collection, including a rigorous evaluation of safety indicators, alternative design features, and intermediate markers, will lay the foundation for a later large-scale study that will be designed, for the first time, to provide Level I evidence that addresses the effectiveness of OSA treatment for reducing CVD morbidity and mortality. (End of Abstract)